The oral mucosa is covered by stratified squamous epithelium. The basal layer of mucosal epithelium has columnar cells with rapid division properties to maintain a constant epithelial population as cells are shed from the surface [4]. The lamina propria underlies the epithelium, which consists of fibroblasts and connective tissue, capillaries, inflammatory cells (macrophages), and extracellular matrix [4, 5]. Radiation-induced oral mucositis is not a simple epithelial process and results from complex pathways embracing all different cellular and tissue compartments of the mucosa. It has been proposed that endothelial and connective tissue damage precedes epithelial changes in irradiated oral mucosa [5].

Radiation directly damages cellular DNA of rapidly dividing cells of the oral basal epithelium and cells in the underlying tissue [6]. Radiation also generates oxidative stress and reactive oxygen species (ROS) that lead to further tissue damage by activating a number of transcription factors such as nuclear factor-κB (NF-κB) in the epithelium, endothelium, macrophages, and mesenchymal cells. Subsequently, the upregulation of genes and the production of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 occur, leading to an injury to the connective tissue, endothelium, and apoptosis of cells within the basal epithelium. Pro-inflammatory cytokines also activate molecular pathways that amplify production of TNF-α, IL-1, and IL-6 and resulted in further tissue damage (positive feedback loop).

Until this stage, the clinical appearance of mucosa seems to be normal, and only the thinning of the mucosa and edema related to acute vascular response may develop and cause early signs and symptoms of mucositis (mild erythema and burning sensation). But as radiation therapy continues, all events from the prior phase result in further injuries and loss of the basal epithelial stem cells with continuing cell loss from the mucosal surface, reducing the cellular population of the mucous membrane. Atrophic changes and breakdown of mucosa occur and patients experience obvious symptoms of mucositis [6–12].

The ulcerative phase of mucositis is accompanied by significant inflammatory cell infiltration. Beside the intrinsic factors, this phase may be affected by extrinsic factors that have reciprocal relation together. Damaged epithelium of the ulcerative mucositis is susceptible to bacterial colonization. Following the colonization with a mixed microbial flora, including mostly gram-negative bacteria, bacterial cell wall products penetrate the injured mucosa and increasingly stimulate pro-inflammatory cytokine release, amplifying the severity of mucositis and tissue injury [6]. When radiation therapy is completed, tissue repair begins with renewal of epithelial proliferation and differentiation and reestablishment of the local microbial flora [13].

In conventional fractioned radiotherapy (2 Gy per fraction daily), mucosal erythema with mild discomfort occurs within 1–2 weeks of treatment at doses of approximately 10–20 Gy [13]. Patchy pseudomembranous formation can develop after 2 weeks (20 Gy), and ulcerative radiation-induced mucositis often arises at doses of more than 30 Gy and peaks during the fourth to fifth week of therapy. This timing of symptom presentation is varied based on treatment schedule. In accelerated radiation therapy, mucositis reaches its peak within 3 weeks [11, 14]. The symptoms usually become more severe with treatment and remain for about 2–3 weeks after the end of therapy at its peak [2, 15]. Healing then begins and may take weeks to months (generally 3–6 weeks) to resolve [16]. However, chronic open wounds recognized as soft-tissue necrosis may occur in a few cases due to excessive depletion of mucosal stem cells depending on their recovery [17].

Several factors have been identified for the development of more severe oral mucositis during radiation therapy. These factors could be related to treatment, tumor, and/or patient characteristics.

The early signs of radiation mucositis are red appearance of the oral mucosa due to dilation of capillaries in the endothelial layer and reduced epithelial thickness. A whitish appearance may be seen due to transient hyperkeratinization prior to erythema. Patients are mostly asymptomatic or complain of a mild burning sensation or intolerance to spices or hot food in this early phase. Erythema (Fig. 6.1) is followed by fibrinous pseudomembranous formation, followed by erosion and ulceration (Fig. 6.2). Under the pseudomembranes, the epithelial surfaces are denuded, and hemorrhage occurs easily. Pseudomembranous ulcerative lesions are very painful, and patients complain of severe pain and difficulty in chewing that interferes with their oral intake or speaking, eventually leading to weight loss.

Oral pain follows a similar pattern of objective clinical findings of oral mucositis but it may begin sooner and reach its peak earlier (between weeks 2 and 4) [2]. Correlation between patient-reported and clinical manifestations of mucositis is low in early parts of treatment [46].

Bacterial infection (usually gram-negative) or viral infections (such as herpes simplex virus (HSV)) and fungal infections (usually candidiasis) can sometimes be superimposed on oral mucositis [13, 37]. Infectious mucosal lesions often extend beyond the field of radiation. An infected oral mucosa usually manifests with a deep ulceration with a yellow-white necrotic center and raised borders. Fungal mucositis presents with white removable fungal plaques [13]; however, erythematous forms may occur and complicate the exact diagnosis [47].

Patients undergoing radiation therapy to the oral cavity should be seen at least once a week. At each visit, patient symptoms and their oral intake should be assessed; their oral mucosa should also be examined.

A variety of assessment scales exist for measurement of oral mucositis. Three of the most commonly utilized scales (Table 6.1) for radiation-induced mucositis are toxicity criteria of the Radiation Therapy Oncology Group (RTOG), the European Organization for Research and Treatment of Cancer (EORTC) [48], the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) [49], and the World Health Organization (WHO) oral toxicity scale [50].

Maintenance of good oral hygiene is critical to preventing oral mucositis. All patients should be informed of proper oral hygiene before starting treatment:

Principles of management consist of patient assessment, oral care, management of oral pain, treatment of secondary infection, and consideration of nutritional support.